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Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox
Open accessAbstract
Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8 + T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4 + T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4 + T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4 + T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4 + T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4 + T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4 + T cells as well as the potential use of these cells in immunotherapies for specific cancers.
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“we observed a significant increase in the total CD4+ T cells expressing IFN-γ (figure 4H) and granzyme B (GZMB; figure 4J),60–65 NK cells (figure 4N), and the amount of GZMB expression in CD8+ T cells (figure 4L) in the post-cryoablated RMS 76-9STINGwt TME as compared with RMS 76-9STING-/- TME in wild-type mice, as was Foxp3+ CD4+ cells (figure 4M).”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [64]
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An immunogenic personal neoantigen vaccine for patients with melanoma
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“Interestingly, in a complementary approach where high-risk resected stage III or stage IV melanoma patients were immunized with pools of long peptides containing predicted neoantigens prioritized based solely on HLA-A or HLA-B predicted binding affinity, neoantigen-specific CD4+ T cell responses were seen in addition…”
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Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer
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Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
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Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma
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Lineage tracking reveals dynamic relationships of T cells in colorectal cancer
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“Th cells can be further divided into Th1, Th17, and Tregs.(177)”
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Metadata
- Authors
- Oh, D. Y., & Fong, L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Fong, Lawrence
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 54
- Issue
- 12
- Pages
- 2701-2711
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC8809482
- OpenAlex
- W4200244347
- Cited by
- 467
- References
- 73
- Citations by year
- 2026: 81 · 2025: 127 · 2024: 116 · 2023: 101 · 2022: 41 · 2021: 1
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- NCI
- National Institutes of Health (K08AI139375)
- Prostate Cancer Foundation (R35CA253175)
- Bavarian Nordic
- Genentech
- Parker Institute for Cancer Immunotherapy
- AbbVie
- Amgen
- Merck
- Merck KGaA
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- cytotoxic CD4+ T cells, antitumor immunity, cytotoxicity mechanism, cancer immunotherapy, infection, autoimmunity
- MeSH terms
- Animals, Cytotoxicity, Immunologic, Humans, Neoplasms, T-Lymphocytes, Cytotoxic, CD4-Positive T-Lymphocytes, Immunotherapy, Adoptive
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